source: https://doi.org/10.7892/boris.142627 | downloaded: 29.12.2021

International Journal of

Molecular Sciences

Review

TRP Channels in Digestive Tract Cancers

Paulina Stokłosa *, Anna Borgström, Sven Kappel and Christine Peinelt

Institute of Biochemistry and Molecular Medicine, National Center of Competence in Research NCCRTransCure, University of Bern, 3012 Bern, Switzerland; anna.borgstroem@ibmm.unibe.ch (A.B.);sven.kappel@ibmm.unibe.ch (S.K.); christine.peinelt@ibmm.unibe.ch (C.P.)* Correspondence: paulina.stoklosa@ibmm.unibe.ch; Tel.: +0041-(0)31-631-34-26

Received: 10 February 2020; Accepted: 6 March 2020; Published: 9 March 2020�����������������

Abstract: Cancers of the digestive tract are among the most prevalent types of cancer. These typesof cancers are often diagnosed at a late stage, which results in a poor prognosis. Currently,many biomedical studies focus on the role of ion channels, in particular transient receptor potential(TRP) channels, in cancer pathophysiology. TRP channels show mostly non-selective permeability tomonovalent and divalent cations. TRP channels are often dysregulated in digestive tract cancers,which can result in alterations of cancer hallmark functions, such as enhanced proliferation, migration,invasion and the inability to induce apoptosis. Therefore, TRP channels could serve as potentialdiagnostic biomarkers. Moreover, TRP channels are mostly expressed on the cell surface and ionchannel targeting drugs do not need to enter the cell, making them attractive candidate drug targets.In this review, we summarize the current knowledge about TRP channels in connection to digestivetract cancers (oral cancer, esophageal cancer, liver cancer, pancreatic cancer, gastric cancer andcolorectal cancer) and give an outlook on the potential of TRP channels as cancer biomarkers ortherapeutic targets.

Keywords: TRP channel; cancer; gastrointestinal tract; apoptosis; cell cycle; migration; invasion;cancer hallmarks

1. Introduction

Digestive malignancies refer to a heterogeneous group of cancers that arise in the gastrointestinaltract and associated organs. Cancers of the colon and rectum, stomach, liver, esophagus, and pancreasare among five of the ten most prevalent cancers and cancer-related causes of death [1]. For 2020,approximately 387,000 new cases of cancer in the digestive system, the oral cavity and the pharynxand 179,000 related deaths have been estimated in the United States [2]. Successful treatment ofthese malignancies largely depends on effective screening tools, such as diagnostic blood, stooland endoscopic tests [3–5]. Therapeutic approaches include surgery, chemo and radiation therapy,hormone therapy; as well as tailored and personalized therapies, which are presently undergoingdevelopment [6–13]. To further advance personalized medicine, many research groups have focusedtheir work on the understanding of the molecular nature of cancer hallmark functions, includingunlimited proliferation, increased viability, migration and invasion of cancer cells, and decreasedability to induce apoptosis [14]. Ion channels mediate numerous responses in cellular physiology andare often dysregulated in various diseases, especially in most types of cancer including cancers of thegastrointestinal tract [15]. Ion channels are often responsible for switching on and off intracellularsignaling pathways, which makes them attractive candidate drug targets. In addition, they are mostlyexpressed on the cell surface, and, as a consequence, ion channel targeting drugs do not need to enterthe cell. In recent decades, members of the transient receptor potential (TRP) channel family have beenproposed as potential biomarkers and/or drug targets in cancer therapy.

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TRP genes were first reported in 1969, when a mutation in the genome of a visually impairedDrosophila melanogaster fruit fly was described. This mutant, called transient receptor potential, had atransient response to steady light, in opposite to sustained electroretinogram, recorded in the wild-typeflies [16]. However, the trp gene was identified and described 20 years later [17]. Since then, numeroushomologous TRP channel family members have been identified and classified into six human TRPchannel subfamilies, including canonical (TRPC), melastatin (TRPM), vanilloid (TRPV), ankyrin (TRPA),polycystic (TRPP), and mucolipin (TRPML) channels [18,19]. Most TRP channels have an essentialrole in the influx of monovalent and divalent cations, such as Na+, Mg2+ and Ca2+, as well as tracemetal ions [18]. Originally, the TRP channel transduction pathways were described for taste andpungent compound perception, thermo- and mechanosensation, pain, osmoregulation, as well ashormone and pheromone signaling [20–24]. Besides their roles in sensory processes, TRP channelsmediate many cellular physiological and pathophysiological functions in cancer and the immunesystem [25–34]. One way of how TRP channels contribute to the pathogenesis of different types ofcancer is through (dys)regulation of intracellular ion levels. For example, the switch from a quiescentcell to a proliferating cell is characterized by global dynamic Ca2+ elevations and the activation ofCa2+ effectors. Cells progressing through the cell cycle are characterized by Ca2+ oscillations [35–38].Additionally, Ca2+ can contribute to the activation or inhibition of apoptosis, as well as the ability ofcells to migrate [35–38]. All TRP proteins share a common topology of six transmembrane segments(S1–S6), with a pore-forming loop between the S5 and S6 segments. The transmembrane segmentstend to share the greatest homology within the particular subfamily, and amino acid sequences inthe pore region of TRP channels are the most highly conserved [18,19]. The amino (N) and carboxyl(C) terminuses are located intracellularly; they vary in length and sequence, and contain diversedomains and motifs, which play a role in channel assembly, activation and regulation. These domainsand motifs can include coiled coils, calmodulin-binding sites, lipid interaction domains, EF hands,or phosphorylation sites, and are highly variable within members of the same subfamily [18,39].Recent advances in cryogenic electron microscopy (cryo-EM) based structural analysis have providedinsights into the architecture of several TRP channels, including TRPA1, TRPPC, TRPM, and TRPVchannels [40–54]. To date, most changes involving TRP channels in cancer do not involve mutationsin the TRP genes but rather increased or decreased levels of expression of functional TRP proteins,depending on the cancer’s stage. Here, we focus on TRP channels, especially members of the TRPC,TRPM, and TRPV subfamilies in digestive malignancies, that are mostly of epithelial origin, includingoral, esophageal, pancreatic, gastric, and colorectal cancer.

2. Oral Cancers

Oral squamous cell carcinoma (SCC) accounts for approximately 90% of cases of oral cancer [55].The oral cavity comes into contact with several sensory stimuli that are known to activate a number ofTRP channels. Capsaicin, the chemical compound responsible for the burning sensation of chili peppers,activates TRPV1 channels. Additionally, pungent mustard oil activates TRPA1, and menthol activatesTRPM8. It has been suggested that these compounds might exhibit chemoprotective features [56–58].In human oral SCC cells, TRPV1–4, TRPV6, TRPA1, TRPM8, and TRPM2 are expressed [59–62].In 2009, the expression levels of TRPV1 were investigated in the human tongue, in tongue SCC,and pre-malignant leukoplakia. Under pre-malignant conditions and in SCC, the TRPV1 proteinexpression was increased [59]. The expression of TRPV1 protein was also shown in human oral SCC.Capsaicin, a TRPV1 agonist, was shown to induce cytotoxicity in oral SCC cells. However, this effectwas independent of TRPV1 conductivity, as these cells did not exhibit an increase in intracellular Ca2+

upon stimulation with capsaicin [63]. Furthermore, it was shown that TRPV1–4 expression levels wereelevated on protein level in different areas of the oral cavity, including the tongue, buccal mucosa,gingiva, and the oral floor, compared to normal oral mucosa. In addition, known risk factors for SCC,such as alcohol consumption and smoking, increased the expression levels of TRPV1–4 mRNAs [61].TRPA1 is expressed in oral SCC, and thymol induces an increase in intracellular Ca2+, which is blocked

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when a TRPA1 antagonist is present. However, the anti-cancerous effects of thymol are not mediatedby TRPA1 [64]. Notably, it has been reported that oral SCC cells may secrete certain lipids that activateTRPA1 and TRPV1 nociceptors and thus mediate SCC-induced neck pain [65]. Cold/menthol-activatedTRPM8 is expressed on protein and mRNA level in oral SCC cell lines. Immunohistochemistry (IHC)analysis showed that TRPM8 localizes not only in the plasma membrane, but also in the endoplasmicreticulum (ER) membrane. Menthol activates TRPM8 in the ER plasma membrane, resulting in aCa2+ release from intracellular Ca2+ stores and store-operated Ca2+ entry. Menthol-activated Ca2+

entry is also partially mediated by TRPM8, and both of these mechanisms can be blocked by aTRPM8-specific inhibitor. Functionally, the inhibition of TRPM8 results in a reduction in oral SCCcell viability, migration and invasion [60]. TRPM2 is another ion channel that contributes to Ca2+

influx and is activated by cADPR, reactive oxygen species (ROS), and 2′-deoxy-ADPR [66,67]. TRPM2protein expression is significantly increased in tongue SCC compared to non-malignant tongue tissues(control or papilloma). In two human tongue SCC cell lines, TRPM2 expression was upregulatedcompared to a non-tumorigenic oral epithelial cell line. The downregulation of TRPM2 decreasedcancer cell migration and increased ROS induced apoptosis [62]. Table 1 summarizes studies in whichthe expression of TRP channels in human tongue and oral tumor samples was described.

Table 1. Expression of transient receptor potential (TRP) channels in human oral cancers.

Type ofCancer Channel

mRNA/Protein(+ Assessment

Method)Sample Size Aim/Outcome + Reference

Oral

TRPV1–4mRNA (qPCR) 37 oral SCC + tissues samples/

compared to normal adjacent tissue

TRPV1–4 mRNA and protein expressionupregulated in oral SCC tissue samples in

comparison to normal tissue [61]protein (IHC)

TRPV1

Protein(IHC + WB)

18 tongue SCC +8 leukoplakia +

7 normal tongue tissues samples

TRPV1 protein and mRNA expressionupregulated in tongue SCC tissue samples in

comparison to normal tissue [59] 1mRNA (qPCR)

Protein (IHC) 3 oral SCC + 3 normal oral mucosatissue samples TRPV1 protein is expressed in oral SCC [63]

TRPM2 Protein (IHC)9 normal tongue +

12 papilloma tongue +23 tongue carcinoma tissue samples

TRPM2 protein is overexpressed in tonguecarcinoma in comparison to normal and

papilloma samples [62]1 Only IHC assessment of protein expression showed upregulation of TRPV1 in leukoplakia in comparison tonormal tissue; data not available for qPCR and WB. IHC, immunohistochemistry; SCC, squamous cell carcinoma;qPCR, quantitative polymerase chain reaction; WB, Western-Blot.

3. Esophgeal Cancer

Esophageal cancer is the eighth most common cancer worldwide [1] and is characterized by apoor prognosis [68]. This type of cancer is classified into two different cancer entities: esophagealsquamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) [1,68–70]. The link betweenthe pathophysiology of esophageal cancer and TRP channel expression has been exclusively made forESCC and includes dysregulation of TRPC6, TRPM7, TRPM8, TRPV1, TRPV2, and TRPV4 expressionlevels. Table 2 summarizes studies in which the expression of TRP channels in human ESCC sampleswas described.

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Table 2. Expression of TRP channels in human esophageal squamous cell carcinoma (ESCC).

Type ofCancer Channel

mRNA/Protein(+ Assessment

Method)Sample Size Aim/Outcome + Reference

Esophageal

TRPC6mRNA (in situhybridization)

55 paraffin-embedded ESSC+ 21 fresh ESCC tissuesamples/compared tonormal adjacent tissue

TRPC6 mRNA and protein areoverexpressed compared tonormal adjacent tissue [71]

Protein (IHC)

TRPM8mRNA (qPCR) 10 ESCC tissue

samples/compared tonormal adjacent tissue

TRPM8 mRNA and proteinare overexpressed comparedto normal adjacent tissue [72]Protein (WB)

TRPM7 Protein (IHC)

52 ESCC tissuesamples/compared to

non-cancerous esophagealepithelia

TRPM7 protein isoverexpressed compared tonon-cancerous esophageal

epithelia (no TRPM7expression detected) [73] 1

TRPV2 Protein (IHC) 62 ESCC tissue samples

Analysis of TRPV2 expression(low/high); worse overall

survival and 5 year survival ofpatients with high TRPV2

protein expression [74]1 The 5 year survival rate of patients with high TRPM7 expression (82.6%) was significantly higher than that of thepatients with low expression (54.6%). ESCC, esophageal squamous cell carcinoma; IHC, immunohistochemistry;qPCR, quantitative polymerase chain reaction; WB, Western-Blot.

TRPC6 mRNA and protein expression levels are increased in human ESCC tissues comparedto normal esophageal tissues. Furthermore, the inhibition of TRPC6 in ESCC cells led to decreasedCa2+ signaling and cell cycle arrest via Cdk1. In addition, the inhibition of TRPC6 decreased tumorformation in a mouse xenograft model [71].

TRPM8 mRNA and protein expression have been reported to be upregulated in ESCC tissuesand ESCC cell lines. The knockdown and inhibition of TRPM8 decrease proliferation of esophagealcancer cells. Moreover, TRPM8 negatively regulates PD-L1 expression through the calcineurin–NFATc3pathway, enabling the immune evasion of ESCC cells [72].

The protein expression of the Ca2+/Mg2+ channel TRPM7was reported to be a good independentprognostic factor for patients with ESCC. Additionally, siRNA-based silencing of TRPM7 in TE6 ESCCcells increased their proliferation, migration, and invasion [73].

TRPV2 mRNA and protein have been found to be overexpressed in ESCC cell lines. In ESCCpatients, higher expression of TRPV2 protein correlates with a worse 5 year overall survival rateafter surgery. The knockdown of TRPV2 in ESCC cells decreased proliferation, cell cycle progression,and the ability to invade and migrate. Moreover, the authors found downregulated WNT/β-catenin orbasal cell carcinoma signaling-related genes [74]. TRPV1 and TRPV4 were both found to be expressedon mRNA and protein level in non-tumorous esophageal squamous cells and overexpressed in ESCCcells. Furthermore, TRPV1 and TRPV4 are functional in these cells, as shown with calcium imagingand whole cell patch clamp techniques. Finally, the overactivation of both channels leads to increasedproliferation and migration of ESCC cells [75].

4. Liver Cancer

Liver can be affected by two types of cancer: hepatocellular carcinoma (HCC) or metastases fromcolorectal cancer. Liver cancer tissue has been reported to express several TRP channels. El Boustanyand colleagues showed that TRPC1, TRPC6, TRPV1, TRPV2, TRPV4, TRPM4, TRPM6, TRPM7,and TRPM8 are expressed on mRNA level in both Huh-7 and HepG2 human hepatoma cell lines,

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while TRPV3 and TRPM5 are only expressed in Huh-7 cells [76]. Table 3 summarizes studies in whichthe expression of TRP channels in human liver cancer samples was described.

Table 3. Expression of TRP channels in human liver cancer samples.

Type ofCancer Channel

mRNA/Protein(+ Assessment

Method)Sample Size Aim/Outcome + Reference

Liver

TRPV1

mRNA(RT-PCR)

6 pairs of HCC tissuesamples/compared tonormal adjacent tissue

6 non-tumor tissues showed TRPV1 mRNAoverexpression; HCC tissue samples showed

downregulation in 4/6 tested [77]

mRNA (in situhybridization)

15 HCC samples/comparedto normal adjacent tissue

TRPV1 expressed in some HCC and normaltissue samples; data non-conclusive [77]

Protein (IHC) 62 HCC tissue samples + 62non-tumor control tissues

High TRPV1 expression was observed in30/62 HCC samples; high TRPV1 expression

was associated with longer disease-freesurvival [77]

TRPV2Protein (IHC) 55 HCC cancer tissue

samplesUpregulation of TRPV2 on mRNA andprotein levels inversely correlated with

histopathologic differentiation [78]mRNA (RT-PCR) 13 paired HCC tumor

mRNA extracts

TRPV4 Protein (IHC)45 HCC tissue

samples/compared tonormal adjacent tissue

TRPV4 protein and mRNA levels higher inHCC tissues than in normal tissues; positivecorrelation between TRPV4 expression; the

histological grade and number of tumors [79]mRNA (qPCR)

TRPC6 Protein (IHC)150 HCC tissue

samples/compared tonormal tissues

TRPC protein upregulated in HCC tissues incomparison to normal tissues [80]

IHC, immunohistochemistry; qPCR, quantitative polymerase chain reaction; RT-PCR, reverse transcriptionpolymerase chain reaction; WB, Western-Blot.

TRPV1 is overexpressed in hepatocarcinoma tissues compared to normal liver tissue. In thesame study, a correlation between TRPV1 protein expression and histopathologic differentiation wasreported. High TRPV1 expression was associated with longer disease-free survival [77]. In addition,TRPV1 was previously shown to modulate migration of HCC cells [81,82]. Furthermore, capsaicininduced an increase in intracellular Ca2+ levels, ROS production, and apoptosis in HepG2 cells [83].The induction of apoptosis in HepG2 cells by capsaicin-induced TRPV1 activation was later furtherconfirmed [84].

Another member of the TRPV subfamily, TRPV2, is also expressed in hepatocarcinoma tissue.TRPV2 expression on mRNA and protein level are increased in moderately and well-differentiatedhepatocarcinoma tissues compared to poorly differentiated tumors. Moreover, a correlation betweenTRPV2 expression and portal vein invasion was confirmed [78]. Interestingly, the expression of TRPV2mRNA and protein levels in HepG2 and Huh-7 cells was reported to increase upon exposure to ROS,specifically H2O2, resulting in an activation of cell death. The elevation of TRPV2 expression led toan inhibition of pro-survival signals (Akt, Nrf2) and, in the early stage of apoptosis, promoted theactivation of pro-death signals (p38, JNK1) [85]. Another study showed that shRNA-based TRPV2knockdown in HepG2 cells enhanced spheroid and colony formation, which was restored by theoverexpression of TRPV2. Additionally, the expression of TRPV2 protein was linked to the stemness ofliver cancer cells, as the knockdown of TRPV2 in HepG2 cells induced the expression of liver cancerstem-like cells (LCSLCs) markers. Moreover, in human hepatoma cell line SMMC-7721, which exhibitslower TRPV2 protein expression than HepG2, reinforced TRPV2 expression led to the reduction ofthe expression of LCSLCs markers and reduced spheroid and colony formation. In line with thesefindings, probenecid, a TRPV2 agonist, also reduced LCSLCs markers expression, as well as spheroidand colony formation. LCSLCs are considered to be good targets for liver cancer therapy, as theyexhibit stem cell properties and are of a highly tumorigenic nature. Therefore, TRPV2 was proposed tobe a potential target in hepatoma therapy [86]. Notably, reduced expression of TRPV2 mRNA and

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protein in poorly differentiated tumors in comparison to higher differentiated hepatoma [78] supportsthe idea that reduced TRPV2 expression promotes the stem-cell features of hepatoma cells during theearly stages of tumor development [86].

Protein and mRNA levels of TRPV4 are elevated in hepatocellular carcinoma tissue comparedwith paired non-tumor tissue. Poorly differentiated HCC tumors displayed stronger TRPV4 expressionand a positive correlation between TRPV4 expression; the histological grade and number of tumorswas described [79]. In addition, with the use of a TRPV4-specific antagonist and agonist, Fang andcolleagues showed that TRPV4 is crucial for HCC cell viability and that its inhibition could causeanti-tumor effects through modulation of the expression of apoptosis-related molecules. Furthermore,in a xenograft mouse model system, the blockage of TRPV4 was shown to decrease tumor size andweight compared to the control group [79].

The downregulation of TRPC1 with shRNA-based interference has been shown to suppress cellproliferation but not migration of HCC cells. In addition to the anti-proliferative effect of TRPC1silencing, Selli and colleagues reported an elevation in store-operated Ca2+ entry [87].

TRPC6 is weakly expressed on mRNA and protein level in normal hepatocytes but stronglyexpressed in liver carcinoma samples. Moreover, high TRPC6 expression has been suggested to beassociated with a higher Tumor Node Metastasis (TNM) classification of tumors [76,80]. TRPC6overexpression in Huh-7 cells leads to increased proliferation [76]. In addition, TGF-β has been shownto induce a formation of the complex between TRPC6 and the type1 Na+/Ca2+ exchanger (NCX1),leading to an increased migration and invasion of HCC. Moreover, a positive correlation was foundbetween the severity of HCC progression and the expression of TRPC6 and NCX1 [80]. Both theinhibition and RNAi downregulation of TRPC6 or NCX1 was able to attenuate TGF-β induced cellmigration or the intrahepatic metastasis of human HCC in an in vivo xenograft mouse model [80].Moreover, Wen and colleagues recently reported a significantly increased TRPC6 mRNA expression inHCC cells upon hypoxia stimulation, doxorubicin treatment, or ionizing radiation [88]. The inhibitionor downregulation of TRPC6 significantly decreased drug resistance to all three stimuli, and TRPC6inhibition could reverse endothelial–mesenchymal transition (EMT), induced by doxorubicin treatment.In line with these findings, TRPC6 interference in vivo enhanced the sensitivity to doxorubicin and ledto slower growth of the cells compared to the control cells [88].

Another study found that bradykinin can activate TRPM7 in HepG2 cells, leading to an influxof Ca2+. TRPM7-mediated Ca2+ influx was necessary for the activity of calpains, which play a rolein migration of HepG2 cells. These findings suggest that TRPM7 could be involved in migration ofliver cancer cells. Notably, treatment with bradykinin resulted in an increase in MMP-2 secretion andenhanced migration [89].

5. Pancreatic Cancer

Pancreatic cancer is usually detected at an advanced stage and, currently, most patients arediagnosed with distant metastases and, therefore, have a poor 5 year survival rate [90,91]. Detection ofpancreatic cancer at an early stage has a favorable impact on long-term survival, as the 5 year survivalof localized pancreatic cancer is about 25% but is only 2% for distant disease [90,91].

An analysis performed by Lin and colleagues revealed that somatic mutations in the TRPM2gene exhibit a negative correlation with pancreatic cancer patient survival rates in comparison tothe group without TRPM2 mutations. Additionally, the higher the TRPM2 mRNA expression in thecancerous tissue, the shorter the survival of the patients. TRPM2 expression was also shown to enhanceproliferation, migration, and invasion of PANC-1 cells, a human pancreatic cancer cell line [92].

In 2007, it was shown that TRPM8 is expressed on mRNA and protein level and mediatesnon-selective cation currents in the human pancreatic neuroendocrine tumor (NET) cell line BON, as wellas in primary NET cell lines [93]. TRPM8 protein was found to be upregulated in human pancreaticadenocarcinoma cell lines and tissues [94,95]. Other studies further confirmed the upregulation ofTRPM8 in pancreatic cancer tissues in human patients compared to adjacent tissues [96,97]. In addition,

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high TRPM8 protein expression was found to be associated with lower overall survival and poordisease free survival values for pancreatic cancer patients [97], as well as positively correlated with thetumor size and stage of pancreatic cancer [94]. Furthermore, it was shown that TRPM8 is required forproliferation of the pancreatic adenocarcinoma cell lines, PANC-1 and BxPC-3, due to the cell cyclearrest in the G0/G1 phase [95]. Another study showed that TRPM8 protein is expressed in PANC-1 cellsin a non-glycosylated form and is functional. Additionally, TRPM8 knockdown with siRNA resulted ina decrease in cell migration [98]. TRPM8 expression in a non-glycosylated form was further confirmedand shown to have an impact on the conductive properties of the channel. Additionally, it wassuggested that the glycosylation patterns in PANC-1 cells could have an impact on proliferation [99].It was also further shown that TRPM8 mediates Ca2+ influx in PANC-1 and BxPC-3 cell lines and playsa role in proliferation as well as migration. Additionally, targeting TRPM8 in PANC-1 and BxPC-3with siRNA resulted in an enhancement of gemcitabine cytotoxicity, which was accompanied by achange in the expression of apoptosis- and gemcitabine metabolism-related proteins [96]. Anotherstudy further showed that targeting TRPM8 with shRNA in BxPC-3 and MIA PaCa-2 resulted in adecrease in invasion [94].

TRPM7 was shown to play a role in the development of the pancreas in a zebra fish model,which was linked to Mg2+ sensitive signaling. These findings could be translated to the pathogenesisof pancreatic adenocarcinoma, in which TRPM7 protein was shown to be overexpressed and necessaryfor Mg2+-regulated proliferation. Targeting TRPM7 with siRNA in PANC-1 and BxPC-3 resultedin a cell cycle arrest in the G0/G1 phase, accompanied by a change in the expression of p21, cyclinG1, and cyclin B1. The role of TRPM7 in the regulation of pancreatic cancer cells proliferation wasalso connected to Mg2+, as supplementation of the culture medium with Mg2+ reversed the decreasein proliferation caused by the knockdown of TRPM7 [100]. TRPM7 does not affect apoptosis inPANC-1 and BxPC-3 [100,101]. However, it plays a role in preventing replicative senescence. TargetingTRPM7 enhances cytotoxicity of the conventionally used chemotherapeutic, gemcitabine, which is apro-apoptotic agent, suggesting that targeting TRPM7 in pancreatic cancer could support standardchemotherapy [101]. Another group showed that TRPM7 mRNA and protein are overexpressedin pancreatic ductal adenocarcinoma compared to healthy pancreatic tissue, and TRPM7 stainingintensity is inversely correlated with patients’ survival. Additionally, the study showed that BxPC-3cells exhibit TRPM7-characteristic non-selective cationic currents and that TRPM7 activity regulatesintracellular Mg2+ levels [102]. Contrary to previous findings [100,101], another study based on thesiRNA targeting of TRPM7 reported no effect on cell viability and proliferation but showed a decrease incell migration [102]. The overexpression of TRPM7 protein in pancreatic cancer was further confirmed,and a correlation was found between TRPM7 expression levels and the size and stage of tumors.Additionally, TRPM7 is overexpressed in pre-malignant tissue. Therefore, the expression of TRPM7could be further investigated as a potential biomarker [103]. Furthermore, high TRPM7 staining inpancreatic ductal adenocarcinoma has been associated with higher TRPM7 protein staining in thelymph nodes, suggesting that TRPM7 might be involved in invasion of pancreatic cancer cells [104].Indeed, TRPM7 has been shown to be involved in the invasion of BxPC-3 cells [103]. Another studyshowed that in PANC-1 and MIA PaCa-2 cell lines, the TRPM7-mediated cation current regulates Mg2+

homeostasis and cell invasion, as TRPM7 knockdown was shown to reduce invasion along with adecrease in MMP2, uPA, and Hsp90α secretion [104].

TRPV1 was shown to be expressed on mRNA and protein level and regulate intracellular Ca2+

levels in pancreatic NET BON-1 cells, and its activity triggered secretion of chromogranin A [105].Furthermore, the TRPV1 agonist, capsaicin, reduced viability and proliferation, and induced apoptosisin NET cells. The cytotoxicity of capsaicin was shown to be due to the disturbance of mitochondrialpotential and the inhibition of ATP production [106]. Similar to the observations in NET cells,TRPV1 overexpression in PANC-1 cells inhibited cell proliferation. Either the overexpression oragonist-induced activation of TRPV1 reduced the expression of epidermal growth factor receptor(EGFR), due to its ubiquitination. Additionally, TRPV1 reduced mRNA expression of two oncogenes,

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KRAS and AKT2 [107]. Another member of the TRPV subfamily, TRPV6, is expressed in BON-1 cellline on mRNA and protein level, and it regulates Ca2+ levels. The downregulation of TRPV6 in BON-1cells, resulted in an inhibition of proliferation and reduced NFAT activation [108]. Furthermore, TRPV6protein expression is elevated in pancreatic cancer tumors compared to non-tumor adjacent tissuesand its high expression correlated with lower survival of the patients. The knockdown of TRPV6 inpancreatic cancer cell lines resulted in a reduced proliferation, induced cell cycle arrest in the G0/G1phase, reduced migration and invasion, as well as increased apoptosis [109].

Table 4. summarizes studies in which the expression of TRP channels in human pancreatic cancersamples was described.

Table 4. Expression of TRP channels in human pancreatic cancer samples.

Type ofCancer Channel

mRNA/Protein(+ Assessment

Method)Sample Size Aim/Outcome + Reference

Pancreatic

TRPM2

mRNA(analysis ofpreviously

published cancergenome studies)

91 pancreatic cancer patients High TRPM2 expression correlated withlower overall survival [92]

TRPM8

Protein (IHC)280 pancreatic

adenocarcinoma tissuemicroarrays

Moderate or high level of TRPM8 proteinexpression in 92% of pancreatic

adenocarcinoma; the expression levels ofTRPM8 positively correlate with the size ofthe primary tumor and tumor stages [94]

Protein (IHC)5 pancreatic adenocarcinomatissue samples/compared to

normal adjacent tissue

TRPM8 protein expression upregulatedcompared to normal tissue [95]

Protein (IHC)mRNA (qPCR)

44 pancreatic adenocarcinomatissue samples/compared to

normal adjacent tissue

TRPM8 protein and mRNA upregulatedcompared to normal tissue [96]

mRNA (qPCR)

110 pancreaticadenocarcinoma tissue

samples/compared to normaladjacent tissue

TRPM8 mRNA upregulated compared tonormal tissue; high TRPM8 protein

expression was found to be associated withlower overall survival and poor disease free

survival values for pancreatic cancerpatients [97]

TRPM7

Protein (IHC)

5 pancreatic adenocarcinomatissue samples/compared to

normal pancreatic tissuesamples

TRPM7 protein upregulated compared tonormal tissue [100]

Protein (IHC)

282 pancreaticadenocarcinoma tissue

microarrays/compared tonormal pancreatic tissue

microarrays

TRPM7 protein upregulated compared tonormal tissue; TRPM7 expression correlates

with the tumor stage [103]

Protein (IHC)mRNA (RT-PCR)

8 tumor pancreatic ductaladenocarcinoma/compared to

6 normal pancreatic tissues

TRPM7 protein and mRNA upregulatedcompared to normal pancreatic tissue [102]

TRPV6 Protein (IHC)76 tumor pancreatic tissue

samples compared to adjacentnormal pancreatic tissues

TRPV6 protein upregulated compared tonormal pancreatic tissue [109]

IHC, immunohistochemistry; qPCR, quantitative polymerase chain reaction; RT-PCR, reverse transcriptionpolymerase chain reaction.

6. Gastric Cancer

Gastric cancer was the third most common cause of cancer-related deaths in 2018, just after lungand colorectal cancer [1]. Most patients with early-stage gastric cancer are asymptomatic; therefore,a diagnosis is often made when the cancer is at an advanced stage and shows metastasis [110]. SeveralTRP channels have been proposed to be involved in the pathogenesis of gastric cancer. The TRPC6channel was shown to be upregulated on protein and mRNA level in human gastric cancer epithelial

Int. J. Mol. Sci. 2020, 21, 1877 9 of 23

cells in comparison to normal gastric epithelial cells. TRPC6-mediated Ca2+ influx in gastric cancercell lines is responsible for regulation of the cell cycle, as the inhibition of TRPC6 resulted in cell cyclearrest in the G2/M phase and inhibited cell growth. The involvement of TRPC6 conductivity in cellcycle regulation was further confirmed in experiments where the TRPC6 dominant-negative mutantwas expressed. Moreover, treatment of nude mice with a TRPC6 blocker resulted in the inhibitionof the development of a xenografted human gastric tumor [111]. Another study suggested a role forTRPC 1/3/6 in the regulation of EMT [112]. Additionally, a newly developed TRPC6 inhibitor showedan anti-tumor effect in nude mice with a xenografted human gastric tumor [113].

Capsaicin has been shown to induce apoptosis in a normal human epithelial gastric cell lineand the gastric cancer cell line AGS. However, AGS cells were found to be more susceptible tocapsaicin-induced apoptosis, which was induced through an increase in mitochondrial permeabilityand activation of Bax and p53. Surprisingly, the capsaicin-induced apoptosis was dependent on Ca2+

influx mediated by TRPV6, rather than TRPV1, a known capsaicin receptor [114].TRPM2 was found to be expressed on mRNA level in gastric cancer patients, and its high

expression was negatively associated with the overall survival of patients. Functional TRPM2 isexpressed in gastric cancer cell lines AGS and MKN-45, and its shRNA based knockdown results inthe inhibition of proliferation and enhancement of apoptosis. Additionally, TRPM2 knockdown wasshown to alter autophagy in AGS cells, which led to mitochondrial dysfunction. The knockdown ofTRPM2 also sensitized AGS and MKN-45 cells to treatment with paclitaxel and doxorubicin, resultingin a further reduction in cell viability. These findings suggest that targeting TRPM2 in combination withstandard chemotherapeutic drugs could be beneficial for the treatment of gastric cancer patients [115].

TRPM7 channel was shown to be expressed in gastric cancer cell lines on mRNA and proteinlevel. AGS gastric cancer cells exhibit TRPM7-like currents, and suppression of these currents bythe unspecific TRPM7 inhibitors, La3+ or 2-APB, resulted in a decrease in cell viability and higherapoptosis rates. Additionally, Mg2+ was necessary for AGS cells survival and growth [116].

Table 5 summarizes studies in which the expression of TRP channels in human gastric cancersamples was described.

Table 5. Expression of TRP channels in human gastric cancer samples.

Type ofCancer Channel

mRNA/Protein(+ Assessment

method)Sample Size Aim/Outcome + Reference

Gastric

TRPC6

Protein (IHC)25 primary gastric cancersamples/compared to4 gastritis samples

TRPC6 mRNA and proteinexpression upregulatedcompared togastritis samples [111]mRNA (in situ

hybridization)10 primary gastriccancer samples

TRPM2mRNA (analysisof online gastriccancer databases)

896 gastric cancer patients;analysis of low TRPM2 vshigh TRPM2 expression

High TRPM2 mRNAexpression high expressionnegatively associated withthe overall survival ofpatients [115]

IHC, immunohistochemistry.

7. Colorectal Cancer

Colorectal cancer (CRC) is one of the most frequent types of cancer and cancer-related cause ofdeath, both in Europe and in the United States [117,118]. Several TRP channels have been shown to bedysregulated in CRC. A study investigating mRNA expression levels of the TRP channels in humanCRC tissue versus normal colon mucosa detected an increase in gene expression of TRPM8, TRPV6,and TRPV1 and a lower expression of TRPV4, TRPM4, TRPV3, TRPC6, and TRPV5 in the tumor tissues

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of CRC compared to normal tissues [119]. Table 6 summarizes studies in which the expression of TRPchannels in human gastric cancer samples was described.

Table 6. Expression of TRP channels in human colorectal cancer (CRC) samples.

Type of Cancer ChannelmRNA/Protein(+ Assessment

Method)Sample Size Aim/Outcome + Reference

Colorectal (CRC)

TRPC1

mRNA (analysisof CRC datasets,available frompublic databases)

656 CRC samplesincluding 47normal samples

High TRPC1 expressioncorrelated with poorprognosis for the patients[120]585 CRC samples

including 19normal samples

TRPV1 Protein (IHC)

10 CRC tissuesamples, 10CRC-adjacenttissue samples, and6 normal subjects

TRPV1 protein expressiondecreased in CRC tissuescompared to normal tissues[121]

TRPM4 Protein (IHC)CRC tumor tissuemicroarrays from379 patients

High TRPM4 proteinexpression was associatedwith unfavorable tumorfeatures characteristic forepithelial-mesenchymaltransition and infiltrativegrowth patterns [122]

TRPM6

mRNA (analysisof CRC datasets,available frompublic databases)

656 CRC samplesincluding 47normal samples TRPM6 mRNA expression

decreased compared tonormal tissue [120]585 CRC samples

including 19normal samples

mRNA (analysisof CRC dataset,available frompublic databases)

585 CRC samplesincluding 19normal samples

TRPM6 mRNA expressiondecreased compared tonormal tissue; high TRPM6mRNA expression positivelycorrelated with overallsurvival [123].

CRC, colorectal cancer; IHC, immunohistochemistry.

TRPC1 ion channel, which displays permeability towards Ca2+ ions, was reported to be upregulatedon mRNA and protein level in CRC cells [124], and its higher mRNA expression in CRC patientshas been correlated with a poor prognosis [120]. The upregulated expression of TRPC1 in CRC hasbeen shown to contribute to an increased Ca2+ influx via store operated Ca2+ entry and higher Ca2+

signaling, which resulted in an increased proliferation, invasion, and survival of CRC cells [124].Furthermore, Ca2+ influx through TRPC1 was also linked to an increased migration of CRC cells [125].Another member of the TRPC subfamily, which conducts Ca2+, TRPC5, was shown to play a rolein the drug resistance of human CRC cell lines. HCT-8 and LoVo cells resistant to 5-fluorouracil(5-FU), which is a commonly used chemotherapeutic in CRC therapy, showed higher expression ofTRPC5 mRNA and protein in comparison to non-resistant cells. Further investigations revealed thatthe TRPC5-mediated Ca2+ influx induces the expression of the ATP-binding cassette subfamily Bmember 1 (ABCB1), a pump overproduced in cancer cells, responsible for the export of cytotoxic drugs.Additionally, TRPC5 promoted nuclear β-catenin localization [126].

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Increasingly, evidence suggests an important role for TRPV1 channel in the physiology andpathophysiology of the intestine. Increased expression of TRPV1 protein was found in the colon ofpatients with inflammatory bowel disease, which was linked to an increased pain sensation [127].However, several studies suggested that the expression and activity of TRPV1 in the intestine hasa protective role in inflammatory states [128–131]. Consistent with these findings, in a mice modelof colitis-associated cancer (CAC), mice that lacked the expression of TRPV1 had a higher incidenceand higher number of tumors in the distant colon. The lack of TRPV1 was also accompanied by anincreased proliferation of colon cells and higher β-catenin localization to the nuclei. Additionally,tumors from mice lacking TRPV1 showed an increased infiltration of inflammatory cells into thetumors, along with an elevated expression of IL-6 and IL-11 and activation of STAT3 and NF-kBsignaling pathways [132]. Further evidence shows that TRPV1 protein expression can have a protectiverole against tumor development. De Jong and colleagues showed that functional TRPV1 is expressedin intestinal epithelial cells and can be activated by capsaicin. TRPV1 activation inhibits EGFR-inducedepithelial cell proliferation via activation of Ca2+/calpain. In a murine model of multiple intestinalneoplasia (ApcMin/+ mice), TRPV1 deficiency promoted intestinal adenoma formation correlated witha reduced lifespan [133], which was consistent with previous findings [132]. In this model, mice thatlack TRPV1 showed higher EGFR phosphorylation and proliferation markers in intestinal epithelialcells, and the deletion of TRPV1 increased the expression of the EGFR-regulated oncogenes, c-Fosand c-Myc. Furthermore, the administration of dietary capsaicin increased the survival of ApcMin/+

mice in a process that was dependent on TRPV1 [133]. Another study suggested that TRPV1 proteinexpression is decreased in CRC tissues. Treatment of HCT116 cell line with capsaicin resulted in aninhibition of proliferation and induced apoptosis through the activation of the tumor suppressor, p53.In this cell line, treatment with capsaicin led to an increase in intracellular Ca2+, possibly throughTRPV1 [121]. On the other hand, studies in human CRC cell lines showed that Fibrulin-5, a componentof ECM, is downregulated in CRC tissues and cell lines. Fibrulin-5 induces apoptosis through thedownregulation of TRPV1 and ROS production [134]. Another study in HT-29 cell line showedthat capsaicin induced apoptosis through PPARγ signaling but without the involvement of TRPV1,since capsazepine, a specific antagonist for the vanilloid receptor, did not inhibit capsaicin inducedapoptosis [135].

TRPM8 is another ion channel responsible for Ca2+ influx into cells and was found to be highlyexpressed on protein level in human CRC cell lines, Caco-2, and HCT116. Furthermore, cannabigerol,a non-psychotropic cannabis-derived cannabinoid, reduces colon cancer progression in vivo andselectively inhibits the growth of CRC cells via interaction with TRPM8 [136].

TRPM4 is an ion channel, which is directly activated by an increase in intracellular Ca2+

concentration, however, is not permeable towards Ca2+. In non-excitable cells, under physiologicalconditions, TRPM4 conducts Na+ into the cell, thereby contributing to plasma membrane depolarization.This, in turn, reduces the driving force for further Ca2+ entry through store operated Ca2+ channels.Therefore, TRPM4 is regarded to be a negative regulator of Ca2+ signaling [137–140]. Reports on mRNAexpression levels of TRPM4 in colorectal cancer either found it to be lower in CRC tissue compared tonormal colon tissue [119], or no differences were detected [141]. However, a recent study investigatingTRPM4 protein expression levels in CRC tissues showed that its high expression correlates with highnumbers of tumor buds and an increased percentage of infiltrative tumor border configuration. Both ofthese features correlate with an increased frequency of vessel invasion and lymph node metastasis,which ultimately lead to an increased probability of disease reoccurrence and cancer related death.TRPM4 protein was also shown to be highly expressed in tumor buds, which were linked to increasedmetastasis in CRC. Furthermore, TRPM4-mediated Na+ influx was shown to regulate cell viability andthe cell cycle of HCT116 cells. In the same study, TRPM4 was also linked to the regulation of CRC cellsmigration and invasion [122].

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There are two Mg2+ channels in the superfamily of TRP channels, TRPM6 and TRPM7, and theiractivity is linked to the pathogenesis of CRC. TRPM6 and TRPM7 are unique ion channels thatmediate Mg2+ homeostasis, as well as proteins, combining an ion channel with a functional α-kinasedomain [29,142–145]. The role of Mg2+ in the pathogenesis of CRC has been reported. Higher Mg2+

intake seems to be associated with a modest reduction in the risk of CRC, in particular, colon cancer [146].However, studies showed that mice receiving Mg2+-deficient diet had a significant retardation of theirprimary tumor growth [147]. Therefore, the relationship between Mg2+ intake and cancer might bemore complex, especially since the relationship of Ca2+:Mg2+ intake is important for the regulation ofcellular responses [148]. At the cellular level, Mg2+ can exhibit either anti- or pro-tumor effects and hasbeen suggested to contribute to different mechanisms involved in carcinogenesis, such as cancer cellproliferation, metabolic reprogramming, the ability to metastasize, and neo-angiogenesis [149,150].Mg2+ was shown to contribute to the regulation of cell proliferation and cell cycle, and Mg2+ deficiencyhas been shown to induce cell cycle arrest in the G0/G1 phase [148]. On these bases, TRPM6 andTRPM7 could be potential players in CRC. Indeed, it was reported that TRPM6 is downregulatedin CRC tissues on mRNA level [120,123], and its higher expression is correlated with an increasedoverall survival [123]. On the other hand, TRPM7 was suggested to be upregulated in CRC on mRNAlevel [151]. Moreover, a single-nucleotide polymorphism that substitutes TRPM7 threonine 1482 forisoleucine (T1482I) increases the risk of the development of colon cancer, particularly in patientswith a high Ca2+/Mg2+ ratio [152]. It must be noted that this mutation does not influence kinaseactivity, nor the channel’s conductivity, but the channel’s sensitivity to Mg2+ [153]. TRPM7 was alsoshown to be overexpressed in CRC cell lines. The downregulation of TRPM7 suppressed CRC cellproliferation, migration, and invasion, as well as triggered cell cycle arrest in the G0/G1 phase, reducedthe S phase, and promoted apoptosis. Furthermore, the decrease in TRPM7 expression in CRC cellsreversed EMT, which was accompanied by a downregulation in N-cadherin and an upregulation ofE-cadherin expression [151]. Mg2+ homeostasis regulation via TRPM6 and TRPM7 was also linkedto the sensitivity of CRC cells to doxorubicin, a common chemotherapeutic agent. A study in theCRC cell line LoVo showed that cells resistant to doxorubicin have increased total intracellular Mg2+

levels compared to sensitive LoVo cells. However, mRNA expression of TRPM6 in cells resistantto doxorubicin was downregulated compared to cells sensitive to doxorubicin. Further, in LoVocells resistant to doxorubicin, TRPM7 is downregulated on protein level, but not on mRNA level,compared to doxorubicin-sensitive LoVo. Therefore, the levels of TRPM6 and TRPM7 are inverselyrelated to the amounts of total intracellular Mg2+. This could be partially explained by the fact thatTRPM7 was markedly reduced in resistant cells because of the activation of calpains, which aredependent on intracellular Ca2+ levels. Free Ca2+ levels are higher in cells resistant to doxorubicin [154].These findings further support the idea that pathogenesis of CRC might be dependent on the Ca2+/Mg2+

ratio [152] and suggest a potential interplay between Ca2+ and Mg2+ transport (dys-) regulation in CRC.Nevertheless, TRPM7 is involved in the modulation of drug resistance in LoVo cells, as downregulationof TRPM7, but not TRPM6, expression enhances viability of LoVo cells exposed to doxorubicin [154].

8. Conclusions and Outlook

Recent studies show that digestive malignancies are characterized by different expression patternsof TRP channels (Figure 1). In general, cancers of the gastrointestinal tract are characterized by a poorprognosis, largely due to late diagnosis, when the disease is at an advanced stage. Therefore, there is aneed to develop novel biomarkers for the detection of early stage diseases. Whether TRP channelscould play such a role remains under investigation, as recent evidence is limited. For example, TRPM7is upregulated in pre-malignant pancreatic cancer compared to normal pancreatic tissue [103], and so itcould potentially serve as a candidate for a pancreatic cancer biomarker. Another candidate for a novelbiomarker could be TRPM4, which was shown to be highly expressed in tumor buds in CRC cancertissues [122]. Currently, there is a need for the introduction of novel additional biomarkers, which couldsupport the TNM staging system [155]. Tumor budding has been suggested to be an additional

Int. J. Mol. Sci. 2020, 21, 1877 13 of 23

prognostic factor, as it is strongly predictive of lymph node metastases, recurrence, and cancer-relateddeath at 5 years [156,157]. Therefore, the expression of TRPM4 could potentially add to the detectionof tumor buds.

Figure 1. Expression of TRP channels in gastrointestinal tract. Overview of TRP channels expressed incancers of the gastrointestinal tract or in the cell lines originating from these types of cancers. ↑Arrowsindicates that the channel is upregulated, while ↓ arrows indicates that the channel is downregulated.For some channels, there was more than one study, showing that they are either upregulated ordownregulated, which is indicated by ↑↓.

Moreover, TRP channels could be potential candidates for therapeutic targets, especially since theyare usually expressed on the cell surface, which makes them accessible to small-molecule inhibitorsand biological molecules, such as monoclonal antibodies and fusion proteins [158–160]. Given thefact that some TRP channels are ubiquitously expressed, the delivery of TRP channel inhibitors tothe tumor sites could be supported by cancer cell-specific drug delivery systems that are currentlybeing developed [161]. TRP channels were shown to regulate cellular responses associated withtumorigenesis (summary in Figure 2). A number of studies show the anti-tumor properties of capsaicin,a TRPV1 channel agonist [106,114,121,133,135]. These findings suggest that the activation of TRPV1could potentially enhance standard therapies. Furthermore, targeting other TRP channels showed anamplification of the effects of commonly used chemotherapeutics [77,96,101,115,126,154], potentially

Int. J. Mol. Sci. 2020, 21, 1877 14 of 23

providing an option for the enhancement of current therapeutic strategies. Currently, several clinicaltrials evaluating ion channel inhibitors and blockers are ongoing [158,162,163]. Furthermore, phase1 clinical studies evaluating TRPV6 channel inhibitor, SOR-C13, in patients with advanced solidepithelial tumors are being evaluated (NCT01578564 and NCT03784677). While the second study is inthe recruiting stage, the results of the first study show that that SOR-C13 was well tolerated. Moreover,of 22 evaluable patients, 54.5% showed stable disease ranging from 2.8 to 12.5 months, which suggestsan anti-tumor activity of SOR-C13 [164]. This is a proof of principle, showing that, in the future, drugstargeting TRP channels in cancer could enter clinical use. Future studies will further investigate thepotential of TRP channels as therapeutic targets in cancer.

Figure 2. Overview of the role of TRP channels in cell functions of cancers of the gastrointestinal tract.TRP channels, which are permeable to monovalent and divalent cations, such as Na+, Ca2+ and Mg2+,are often dysregulated in cancer cells. These can lead to enhancement/suppression of proliferation,migration and invasion, cell cycle progression, and apoptosis. Channels with activity promoting aparticular function are marked in green. Channels with activity suppressing a particular function aremarked in red.

Author Contributions: Concept and idea C.P. and P.S.; preparation of figures and tables P.S.; A.B., S.K., C.P. andP.S. wrote the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding: We acknowledge funding by the Swiss National Science Foundation (NCCR TransCure and31003A_173155/1).

Acknowledgments: Figure 1 was generated with Smart PPT (https://smart.servier.com/).

Conflicts of Interest: The authors declare no conflict of interest.

Int. J. Mol. Sci. 2020, 21, 1877 15 of 23

Abbreviations

5-FU 5-FluorouracilABCB1 ATP-Binding Cassette Subfamily B Member 1Ca2+ Calcium IonsCAC Colitis-Associated CancerCRC Colorectal CancerCryo-EM Cryogenic Electron MicroscopyEAC Esophageal AdenocarcinomaEGFR Epidermal Growth Factor ReceptorEMT Endothelial–Mesenchymal TransitionER Endoplasmic ReticulumESCC Esophageal Squamous Cell CarcinomaHCC Hepatocellular CarcinomaIHC ImmunohistochemistryLa3+ Lanthanum IonsLCSLCs Liver Cancer Stem-Like CellsMg2+ Magnesium IonNa+ Sodium IonsNET Neuroendocrine TumorROS Reactive Oxygen SpeciesSCC Squamus Cell CarcinomaTNM Tumor Node MetastasisTRP Transient Receptor PotentialTRPA Transient Receptor Potential AnkyrinTRPC Transient Receptor Potential CanonicalTRPM Transient Receptor Potential MelastatinTRPML Transient Receptor Potential MucolipinTRPP Transient Receptor Potential PolycysticTRPV Transient Receptor Potential VanilloidWB Western-Blot

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